General Synthesis of Secondary Alkylamines by Reductive Alkylation of Nitriles by Aldehydes and Ketones

Article abstract of DOI:10.1002/chem.202004755

The development of C?N bond formation reactions is highly desirable due to their importance in biology and chemistry. Recent progress in 3d metal catalysis is indicative of unique selectivity patterns that may permit solving challenges of chemical synthesis. We report here on a catalytic C?N bond formation reaction—the reductive alkylation of nitriles. Aldehydes or ketones and nitriles, all abundantly available and low-cost starting materials, undergo a reductive coupling to form secondary alkylamines and inexpensive hydrogen is used as the reducing agent. The reaction has a very broad scope and many functional groups, including hydrogenation-sensitive examples, are tolerated. We developed a novel cobalt catalyst, which is nanostructured, reusable, and easy to handle. The key seems the earth-abundant metal in combination with a porous support material, N-doped SiC, synthesized from acrylonitrile and a commercially available polycarbosilane.

Full text of DOI:10.1002/chem.202004755

Accepted Article
Accepted Article
Title: General synthesis of secondary alkyl amines via reductive
alkylation of nitriles by aldehydes and ketones
Authors: Rhett Kempe, Timon Schönauer, Sabrina L. J. Thomä, Leah
Kaiser, and Mirijam Zobel
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To be cited as: Chem. Eur. J. 10.1002/chem.202004755
Link to VoR: https://doi.org/10.1002/chem.202004755
01/2020

10.1002/chem.202004755
Chemistry - A European Journal
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General synthesis of secondary alkyl amines via reductive
alkylation of nitriles by aldehydes and ketones
Timon Schönauer,[a] Sabrina L. J. Thomä,[b] Leah Kaiser,[a] Mirijam Zobel,[b] and Rhett Kempe[a]*
[a]
T. Schönauer, L. Kaiser, Prof. Dr. R. Kempe
Inorganic Chemistry II – Catalyst Design
University of Bayreuth
95440 Bayreuth (Germany)
E-mail: kempe@uni-bayreuth.de
S. L. Thomä, M. Zobel
[b]
Mesostructured Materials
Department of Chemistry
University of Bayreuth
95440 Bayreuth (Germany)
Supporting information for this article is given via a link at the end of the document.
Abstract: The development of C-N bond formation reactions is highly
desirable due to their importance in biology and chemistry. Recent
progress in 3d metal catalysis is indicative of unique selectivity
patterns that may permit solving challenges of chemical synthesis. We
report here on a catalytic C-N bond formation reaction – the reductive
alkylation of nitriles. Aldehydes or ketones and nitriles, all abundantly
available and low-cost starting materials, undergo a reductive
coupling to form secondary alkyl amines and inexpensive hydrogen is
used as the reducing agent. The reaction has a very broad scope and
many functional groups, including hydrogenation-sensitive examples,
are tolerated. We developed a novel cobalt catalyst, which is
nanostructured, reusable, and easy to handle. The key seems the
earth-abundant metal in combination with a porous support material,
N-doped SiC, synthesized from acrylonitrile and a commercially
available polycarbosilane.
groups, including hydrogenation-sensitive examples, are
tolerated. We had to develop a novel catalyst which is
nanostructured, reusable, and easy to handle. The key is the
earth-abundant metal cobalt (Co) in combination with a porous
support material, N-doped SiC synthesized from acrylonitrile and
a commercially available polycarbosilane. The catalyst has a
distinct selectivity pattern; it permits the selective hydrogenation
of aliphatic or aromatic nitriles while barely reducing aldehydes or
ketones. In addition, the transiently formed imine intermediate is
efficiently hydrogenated.
C-N bond formation reactions are of fundamental interest in
chemistry and biology, and amines are very important compounds
and key functional groups in many bulk and fine chemicals,[1]
drugs[2] and materials.[3] Differently substituted secondary alkyl
amines, examples of pharmaceuticals are shown in Scheme 1A,
are challenging to synthesize. Most of the existing catalytic
methods, such as borrowing hydrogen or hydrogen
autotransfer,[4,5] reductive amination,[6,7] hydroaminomethylation[8]
and hydroamination,[9,10] albeit intensively investigated, start
already from an amine (Scheme 1B) and are restricted regarding
the synthesis of secondary alkyl amines.[11] The hydrogenation of
amides is an alternative (Scheme 1C), since it does not require
an amine as starting material,[12,13] but again the synthesis of
differently substituted secondary alkyl amines is rarely
reported.[14] The use of catalysts based on earth-abundant metals
such as Mn, Fe or Co in reactions classically associated with rare
noble metals is also of fundamental interest.[15-23]
We report herein that the reductive alkylation of nitriles by
aldehydes or ketones permits the general synthesis of secondary
alkyl amines. The reaction has a broad scope. Aromatic or
aliphatic nitriles and benzylic or aliphatic aldehydes or ketones –
dialkyl, diaryl or arylalkyl substituted – can be employed. In
addition, we demonstrated the synthesis and modification of
bioactive compounds and pharmaceuticals. Many functional
Scheme 1. A) Examples of secondary dialkyl amine motifs in pharmaceuticals.
B/C) Examples of the catalytic synthesis of secondary alkyl amines. These
methods can be used to synthesize secondary alkyl amines but the scopes are
mostly demonstrated for aryl-alkyl amines of tertiary alkyl amines (borrowing
hydrogen/hydrogen
hydroaminomethylation, hydrogenation of amides). The intermolecular
hydroamination of alkyl amines and olefins is challenging.
D) Catalytic reaction introduced herein.
autotransfer,
reductive
alkylation
and
Attempts to reductively link nitriles and carbonyl compounds in the
gas phase[24] indicate that this high-temperature approach is
1
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extremely limited in conversion, scope, and functional group
tolerance. Based on the inspiring development of Co catalysts for
the selective hydrogenation of nitriles,[25-30] we expected that a Co
catalyst could also be the key to develop a broadly applicable
catalytic process for the reductive alkylation of nitriles. Co
catalysts have also been employed successfully in reductive
amination reactions, the coupling of amines or ammonia and
aldehydes or ketones in the presence of hydrogen as the reducing
agent.[27,31-41] In addition, the Co catalyzed transfer hydrogenation
and coupling has been described.[42]
and N-SiC (Table 1, entries 4 and 6). In addition, we investigated
different catalyst supports (Table 1, entries 8 till 10; Table S13),
which are all significantly less active.
Our Co catalyst (Co/N-SiC) was synthesized as shown in
Figure 1A. Firstly, we synthesized the N-doped SiC support (N-
SiC), which contains 8 atom% (at%) nitrogen, as determined by
elemental analysis, using a modified literature procedure.[43,44]
Secondly, the N-SiC material was wet impregnated with a solution
of Co(NO3)2 in water. After the evaporation of the solvent, the
sample was pyrolyzed under nitrogen flow at 700 °C followed by
a reduction step (N2/H2, 90/10) at 550 °C (Figure 1A). Inductively
coupled plasma optical emission spectrometry indicated
4.7 weight% (wt%) Co in the catalyst material. Homogeneously
distributed Co nanoparticles with an average particle size of 6 nm
were determined with transmission electron microscopy
(Figure 1B). The catalyst has a specific surface area (Brunauer-
Emmet-Teller) of 367 m2/g with primarily micropores and about
9 % mesopores. X-ray photoelectron spectroscopy analysis
confirms the presence of metallic Co species and oxi(hydroxide)
Co species at the surface of the Co nanoparticles (Figure 1C).
High resolution transmission electron microscopy of the Co
nanoparticles confirms that the core of these particles is metallic
Co (cubic phase, Figure 1D) and indicate an embedding of the Co
nanoparticles into the N-SiC support. In the diffraction data, I(Q),
of the catalyst (Co/N-SiC), the broad reflexes of graphite are still
visible (Figure 1E). Additionally, some reflexes due to Cobalt arise
in the black curve. The first reflex (002) of the graphitic support is
shifted slightly to lower Q values in the catalyst material due to the
loading with Cobalt compared to the bare N-SiC support,
indicating expansion of the graphite interlayer spacing upon
catalyst loading. A biphasic refinement of the d-PDF data (Co/N-
SiC – N-SiC) reveals the coexistence of crystalline Co fcc
nanoparticles with diameters of 5.4 nm and smaller CoO fcc
domains, with a phase ratio of Co particles to CoO domains of
about 6 : 1.
Figure 1. Synthesis and characterization of the Co catalyst denoted as Co/N-
SiC. A) Preparation of the cobalt (Co) catalyst. (a) Wet impregnation of N-SiC
with an aqueous solution of Co(NO3)2. (b) Pyrolysis of the impregnated N-SiC
under a nitrogen atmosphere at 700 °C and reduction of the pyrolyzed sample
in the presence of hydrogen at 550 °C. B) Transmission electron microscopy
analysis of the Co/N-SiC catalyst and Co nanoparticle size distribution.
Homogeneously dispersed Co nanoparticles with an average particle size of
6 nm. C) X-ray photoelectron spectroscopy analysis verifies the presence of
metallic Co and oxi(hydroxide) Co species (about 70 %) at the surface of the Co
nanoparticles. D) Characterization of the Co nanoparticles by high resolution
transmission electron microscopy indicates that they are embedded in the N-
SiC support and metallic E) XRD data of catalyst Co/N-SiC (black) and support
N-SiC material (green), together with their difference (catalyst – support, in red).
F) PDF refinement of the d-PDF (Co/N-SiC – N-SiC), showing the contributions
of the Co fcc phase (green) and of the CoO fcc phase (pink) to the biphasic fit
(in offset for clarity), together with the difference curve (grey) only containing
high frequency noise.
The other supports led to inactive catalysts for which we could not
observe any product formation under these conditions. The
combination of Co(NO3)2 and the porous support material N-SiC
seem essential for the activity in the reductive alkylation of nitriles
with carbonyl compounds under the optimized and mild conditions.
We expected mild conditions to be crucial in order to achieve a
desirable level of tolerance of functional groups.
We were interested in exploring the substrate scope and the
functional group tolerance of our Co/N-SiC catalyst next. Isolated
yields of the secondary amines were given for the corresponding
hydrochloride salts. Reductive alkylation of benzonitrile with
various aldehydes (Figure 2, products 1-19). The secondary
amines using 4-methylbenzaldehyde (electron-donating group)
and 4-chlorobenzaldehyde (electron-withdrawing group) were
isolated in 99% yield (Figure 2, product 1). In addition, the
influence of the substituent position was investigated by
converting 2-, 3- or 4-methylbenzaldehyde and 2-, 3- or 4-
chlorobenzaldehyde. meta-Substituted benzaldehydes showed
no influence on the catalytic activity (Figure 2, products 2, 5), but
a decrease in the product yields were observed for sterically more
demanding 2-methylbenzaldehyde and 2-chlorobenzaldehyde
The reductive alkylation of benzonitrile with 4-
methylbenzaldehyde was chosen as a benchmark reaction for the
optimization of the reaction conditions (Table 1, top). The most
active catalyst based on the yield of product in a given time was
obtained by wet impregnation of N-SiC with Co(NO3)2 and a
pyrolysis temperature of 700 °C (Table 1, entry 3). Varying the
solvent (2-methyltetrahydrofuran, diglyme, dioxane, triethylamine,
methylcyclohexane, ethanol, toluene, water, isopropanol,
pyridine), temperature, hydrogen pressure and ratio of nitrile to
aldehyde led to
a
90 % formation of [N-benzyl-1-(p-
tolyl)methanamine] in 2-methyltetrahydrofuran at 100 °C at a
hydrogen pressure of 1.5 MPa and a nitrile-to-aldehyde ratio of
1:2 (Table S6-9). The replacement of the metal source with other
Co compounds led to a decrease in the yield of secondary amine
(Table 1, entries 1 and 2). A minor decrease in activity was
observed by using catalysts with Co(OAc)2 (OAcH = acetic acid)
and Co(acac)2 (acacH
=
pentane-2,4-dione). Pyrolysis
temperatures of 600 and 800 °C led to a significant decrease in
the catalytic activity of the catalysts synthesized from Co(NO3)2
2
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(Figure 2, products 3, 7). In addition, other electron-withdrawing
substituents, such as fluorides and bromides, were tolerated well;
this was indicative, especially for bromide 8, that dehalogenation
is of minor relevance (Figure 2, products 4-8). The tert-butyl
substituent in the para position of benzaldehyde showed no
influence on the product formation and the corresponding amine
9 was isolated in 99 % yield.
electron-donating methoxy substituent in the para position had no
negative influence on the yield of the corresponding amine, which
was isolated in 99 % yield (Figure 2, product 29).
Benzylic aldehyde variation
Table 1. Catalyst screening.
4: 91 %
8: 86 %
5: 4-Cl, 99 %
6: 3-Cl, 99 %
7: 2-Cl, 93 %
1: 4-CH3, 99 %
2: 3-CH3, 99 %
3: 2-CH3, 89 %
Entry
Metal source
Support
Pyrolysis
Yield [%]
temperature [°C]
1[a]
2[a]
3[a]
4[b]
5[b]
6[b]
7[c]
8[b]
Co(OAc)2· 6 H2O
Co(acac)2
N-SiC
N-SiC
N-SiC
N-SiC
N-SiC
N-SiC
N-SiC
700
700
700
600
700
800
-
71
70
87
48
90
60
0
10: 99 %
9: 99 %
Co(NO3)2· 6 H2O
Co(NO3)2· 6 H2O
Co(NO3)2· 6 H2O
Co(NO3)2· 6 H2O
-
12: 99 %
11: 99 %
13: 97 %
Aliphatic aldehyde variation
18: 65 %
19: 70 %
14: n=3, 64 %
15: n=5, 60 %
16: n=8, 62 %
17: n=10, 67 %
Co(NO3)2· 6 H2O
Pyrolyzed
700
0
polyacrylonitrile
Nitrile variation
9[b]
Co(NO3)2· 6 H2O
Co(NO3)2· 6 H2O
Activated
charcoal
700
700
0
0
20: 4-CH3, 99 %
21: 3-CH3, 96 %
22: 2-CH3, 90 %
23: 99 %
27: 99 %
24: 4-Cl, 99 %
25: 3-Cl, 99 %
26: 2-Cl, 99 %
10[b]
γ-Al2O3
[a] Reaction conditions: 5.0 mol% Co (37 mg catalyst, 4.0 wt% Co, 0.025 mmol
Co, 1.47 mg Co), 0.5 mmol benzonitrile, 1.0 mmol 4-methylbenzaldehyde, 2 mL
2-methyltetrahydrofuran (2-MTHF), 90 °C, 1.5 MPa H2, 16 h. [b] conditions as
above with only 3 mL 2-methyltetrahydrofuran instead of 2 mL. Yields were
determined by gas chromatography using n-dodecane as an internal standard.
Abbreviations in entries 1 and 2 are explained in the text.
28: 84 %
31: 84 %
32: 99 %
29: 4-OCH3, 99 %
30: 3-OCH3, 90 %
Figure 2. Scope of secondary amines using aromatic nitriles and aldehydes.
Reaction conditions: 5.0 mol% Co (74 mg Co/N-SiC, 4.0 wt% Co, 0.05 mmol Co,
2.95 mg Co), 1.0 mmol nitrile, 3.0 mmol aldehyde, 6 mL 2-
methyltetrahydrofuran, 100 °C, 1.5 MPa H2, 20 h. Isolated yields are given for
the corresponding hydrochloride salts.
Boronic esters, such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzaldehyde, are of special importance, since they are
common compounds for cross-coupling reactions and one
example could be isolated in excellent yield (Figure 2, 10).
Secondary amines with methoxy and benzyloxy substituents,
which are used to protect hydroxyl groups, were also isolated in
nearly quantitative yields (Figure 2, products 11, 12). Cyclic
acetals, such as piperonal, which are common protective groups
for carbonyl groups, were also tolerated (Figure 2, product 13). In
addition, purely aliphatic aldehydes can be employed (Figure 2,
products 14-19) albeit with lower isolated yields. Reductive
alkylation of various benzonitriles and benzaldehyde. Methyl
group and chloro-substituted benzonitriles were used to
investigate the substituent position effect for both electron-
donating and -withdrawing substituents (Figure 2, products 20-22
and 24-26). By converting 2-, 3- or 4-methylbenzonitrile, the yield
decreases gradually from para- via meta- to ortho-substituted
nitriles (Figure 2, products 20-22). This trend could not be
observed at the chloro-substituted nitriles, as the corresponding
amines were isolated in 99 % yield (Figure 2, products 24-26). A
decrease of the product yield was observed by converting 2,6-
difluorobenzonitrile, which we believe is due to the two electron-
withdrawing fluoro substituents (Figure 2, product 28). The
However, a slight decrease in the yield could be observed for the
methoxy substituent in the meta position (Figure 2, product 30).
The naphthalene-based nitrile can be converted in good yields to
the corresponding secondary amine 31. To our delight, the
reductive alkylation of an aromatic O-heterocycle proceeded very
well and the corresponding amine 32 was isolated in nearly
quantitative yield. Reductive alkylation of aliphatic nitriles with
various aldehydes (Figure 3). As before, the influence of the
substituent position was investigated with the methyl- and chloro-
substituted benzaldehydes (Figure 3, products 33-35, 37-39). The
same trend was observed, but the yields of the methyl-substituted
secondary amines 33, 34 and 35 were slightly lower, due to the
lower reactivity of the aliphatic nitrile. The secondary amines with
the electron-withdrawing chloro substituents at the 2-, 3- or 4-
position were obtained in 96–99 % isolated yield (Figure 3,
products 37-39). Fluorinated and brominated benzaldehydes
were smoothly converted in the corresponding amines 36 and 40
in good yields. The secondary amine 41 with the electron-
donating methoxy substituent in the para position was isolated in
96 % yield. 4-Benzyloxybenzaldehyde was converted selectively
3
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to product 42 in nearly quantitative yield without a significant
amount of hydrogenolytic ether cleavage. Piperonal was
converted to the corresponding amine 43 in very good yield, no
cleavage of the acetal was observed and a yield of 99 % was
observed for 4-tert-butylbenzaldehyde (Figure 3, product 44).
Combination of an aromatic nitrile with diaryl, aryl-alkyl and dialkyl ketones[a]
55: 71 %
56: 69 %
57: 65 %
58: 85 %
Combination of an aliphatic nitrile with diaryl, aryl-alkyl and dialkyl ketones[a]
Benzylic aldehyde variation
33: 4-CH3, 94 %
34: 3-CH3, 91 %
35: 2-CH3, 82 %
37: 4-Cl, 99 %
38: 3-Cl, 99 %
39: 2-Cl, 96 %
36: 82 %
40: 79 %
62: 70 %
59: 62 %
60: 61 %
61: 57 %
Modification and synthesis of biologically active molecules [a]
44: 99 %
41: 96 %
42: 99 %
43: 89 %
Aldehyde and aliphatic nitrile variation
63: -C7H7, 78 %
64: -C5H11, 77 %
67: 66 %[b]
(Tecalcet)
65: -C7H7, 76 %
66: -C5H11, 72 %
45: n = 2; 99 %
46: n = 3; 99 %
47: 84 %
50: n = 2, o = 10, 51 %
51: n = 3, o = 3, 54 %
52: n = 3, o = 5, 47 %
53: n = 3, o = 10, 62 %
54: n = 3, o = 11, 59 %
48: 82 %
49: 62 %
70: -C7H7, 73 %
71: -C5H11, 69 %
72: -C7H7, 76 %
73: -C5H11, 73 %
68: -C7H7, 80 %
69: -C5H11, 74 %
Figure 3. Scope of secondary amines using aromatic nitriles and aldehydes.
Reaction conditions: 5.0 mol% Co (74 mg Co/N-SiC, 4.0 wt% Co, 0.05 mmol Co,
2.95 mg Co), 1.0 mmol nitrile, 3.0 mmol aldehyde, 6 mL 2-
methyltetrahydrofuran, 100 °C, 1.5 MPa H2, 20 h. Isolated yields are given for
the corresponding hydrochloride salts.
Figure 4. Reductive alkylation of nitriles using ketones and modifications and
synthesis of biologically active molecules. [a] Reaction conditions: 8.0 mol% Co
(118 mg Co/N-SiC, 4.0 wt% Co, 0.08 mmol Co, 4.71 mg Co), 1.0 mmol nitrile,
3.0 mmol ketone, 6 mL 2-methyltetrahydrofuran, 110 °C, 1.5 MPa H2, 20 h.
Isolated yields are given for the corresponding hydrochloride salts. [b] 130 °C.
We then varied the aliphatic nitrile and combined it with numerous,
mostly purely aliphatic aldehydes. Purely aliphatic nitriles of
different chain lengths were linked smoothly with benzaldehyde
and the secondary amines were isolated in yields of 99 %
(Figure 3, products 45, 46). The synthesis of such alkyl-benzyl
amines seems more efficient if an aliphatic nitrile is used instead
of an aliphatic aldehyde. A nitrile with a cyclohexane substituent
was converted to the product 47 in good yields too. The sterically
demanding pivalonnitrile reacts well and the coupling product with
benzaldehyde was obtained in 82 % yield (Figure 3, product 48).
The unsaturated secondary amine 49, which was synthesized
from valeronitril and citronellal, was still isolated in an acceptable
isolated yield of 62 %. Various pure aliphatic nitriles and
aldehydes with different chain lengths were smoothly converted
to the corresponding amines (Figure 3, products 50-54); no
influence of the chain length on the yield were observed.
Reductive alkylation of nitriles with ketones. Here, the imine
intermediate formed after the condensation is sterically more
protected and, thus, more difficult to hydrogenate. Higher reaction
temperatures (110 °C) and catalyst loadings of 8 mol% Co were
required to obtain good yields. We systematically explored the
coupling of an aromatic nitrile, namely, benzonitrile or a purely
aliphatic nitrile, namely, pentanenitrile with a diaryl, aryl-alkyl,
dialkyl or cyclic ketone. Isolated yields between 57 and 81 % were
obtained (Figure 4, product 55 till 62). The yield of the secondary
amines in the reductive alkylation of benzonitrile decreases
gradually from diaryl via aryl-alky to dialkyl ketones (Figure 4,
products 55-57). The cyclic ketone was converted smoothly in the
secondary amine 58. The yield (85 %) was, compared to the other
ketones, higher due to a smaller steric demand.
The same trends but lower isolated yields were observed for the
reaction of the aliphatic nitrile pentanenitrile with the same
ketones (Figure 4, products 59-62). Modification and synthesis of
biologically active molecules. Nabumentone and pentoxifylline,
common drug molecules, were converted to the respective
amines in up to 78 % isolated yield (Figure 4, products 63-66). To
our delight, pentoxifylline was converted without hydrogenation of
the C=O bond. Our synthesis protocol may also be applied to
synthesize biologically active molecules. Tecalcet, which is used
as a calcimimetic agent, can be synthesized from the two
commercially available educts 2-chlorohydrocinnamonitrile and 3-
methoxyacetophenon in 66 % isolated yield (Figure 4, product 67).
Nitriles can also be alkylated with various steroid derivatives. The
reductive alkylation of benzonitrile and valeronitrile with estrone,
stanolone and testosterone proceeded smoothly, and the
products were obtained in yields up to 80 % (Figure 4, products
68-73). Testosterone, which contains the C-C double bond, was
converted into the corresponding unsaturated amines 72 and 73.
The yields of the products, which were synthesized with an
aliphatic nitrile, were slightly lower than those obtained with an
aromatic nitrile. Various tests were performed to demonstrate the
catalyst stability and leaching of cobalt species (see SI). The
reductive alkylation of benzonitrile with 4-methylbenzaldehyde at
about 65 % yield of product was chosen to demonstrate the
reusability of the catalyst and to establish its efficiency. Five
consecutive runs showed no decrease in the catalytic activity
(Figure S10). An upscaling of the reaction was performed using
various substrates. Therefore, 5 mmol of the nitriles was
converted into the secondary alkyl amines on a gram scale. No
decrease of the yield obtained was observed as the reaction was
upscaled (Table S14).
4
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[11] We analyzed the product scope discussed in the review articles cited.
Borrowing hydrogen or hydrogen autotransfer and reductive amination
is strong regarding the synthesis of aryl-alkyl amines or primary amines
and about 10 % of the reported scope are secondary alkyl amines,
mostly with significantly lower isolated yields. Hydroaminomethylation
has been reported dominantly for the synthesis of tertiary alkyl amines
and rarely for that of aryl-alkyl amines. The intermolecular
hydroamination of alkyl amines and olefins giving secondary alkyl
amines is challenging and much less explored in comparison to the
intramolecular version and alkyne hydroaminations.
[12] E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon, D. Milstein, J. Am.
Chem. Soc. 2010, 132, 16756–16758.
[13] J. M. John, S. H. Bergens, Angew. Chem. Int. Ed. 2011, 50, 10377–
10380; Angew. Chem. 2011, 123, 10561-10564.
[14] J. R. Cabrero-Antonino, R. Adam, V. Papa, M. Beller, Nat. Commun.
2020, 11, 3893-3911.
[15] G. A. Filonenko, R. van Putten, E. J. M. Hensen, E. A. Pidko, Chem.
Soc. Rev. 2018, 47, 1459–1483.
[16] F. Kallmeier, R. Kempe, Angew. Chem. Int. Ed. 2018, 57, 46–60;
Angew. Chem. 2018, 130, 48-63.
[17] J.-B. Peng, F.-P. Wu, X.-F. Wu, Chem. Rev. 2019, 119, 2090-2127.
[18] P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann,
Chem. Rev. 2019, 119, 2192-2452.
[19] K. D. Vogiatzis, M. V. Polynski, J. K. Kirkland, J. Townsend, A.
Hashemi, C. Liu, E. A. Pidko, Chem. Rev. 2019, 119, 2453-2523.
[20] D. Wei, C. Darcel, Chem. Rev. 2019, 119, 2550-2610.
[21] D. Formenti, F. Ferretti, F. K. Scharnagl, M. Beller, Chem. Rev. 2019,
119, 2611-2680.
[22] L. Alig, M. Fritz, S. Schneider, Chem. Rev. 2019, 119, 2681-2751.
[23] W. Ai, R. Zhong, X. Liu, Q. Liu, Chem. Rev. 2019, 119, 2876-2953.
[24] V. A. Tarasevich, N. G. Kozlov, Russ. Chem. Rev. 1999, 68, 55–72.
[25] A. Mukherjee, D. Srimani, S. Chakraborty, Y. Ben-David, D. Milstein, J.
Am. Chem. Soc. 2015, 137, 8888–8891.
Scheme 2. Proposed hydrogenation-condensation-hydrogenation pathway
regarding the reductive alkylation of nitriles with carbonyl compounds (top).
Mechanistic investigations (bottom). Reaction conditions: 5.0 mol% Co (37 mg
catalyst, 4.0 wt% Co, 0.025 mmol Co, 1.47 mg Co), 0.5 mmol benzonitrile, 1.5
mmol 4-methylbenzaldehyde, 3 mL 2-methyltetrahydrofuran, 80 °C, 1.5 MPa H2,
16 h. Under these conditions, products and intermediates are obtained in the
yields given. These yields were determined by gas chromatography using n-
dodecane as an internal standard.
We propose
a
hydrogenation-condensation-hydrogenation
[26] F. Chen, C. Topf, J. Radnik, C. Kreyenschulte, H. Lund, M. Schneider,
A.-E. Surkus, L. He, K. Junge, M. Beller, J. Am. Chem. Soc. 2016, 138,
8781–8788.
[27] R. Adam, C. Bheeter, J. Cabrero-Antonino, K. Junge, R. Jackstell, M.
Beller, ChemSusChem 2017, 10, 842–846.
[28] K. Tokmic, B. J. Jackson, A. Salazar, T. J. Woods, A. R. Fout, J. Am.
Chem. Soc. 2017, 139, 13554–13561.
[29] P. Ji, K. Manna, Z. Lin, X. Feng, A. Urban, Y. Song, W. Lin, J. Am.
Chem. Soc. 2017, 139, 7004–7011.
[30] R. Ferraccioli, D. Borovika, A.-E. Surkus, C. Kreyenschulte, C. Topf, M.
Beller, Catal. Sci. Technol. 2018, 2, 499–507.
[31] A. Skita, F. Keil, W. Stühmer, Ber. 1942, 75, 1696-1702.
[32] T. Stemmler, F. A. Westerhaus, A.-E. Surkus, M.-M. Pohl, K. Junge, M.
Beller, Green Chem. 2014, 16, 4535-4540.
[33] S. Pisiewicz, T. Stemmler, A.-E. Surkus, K. Junge, M. Beller,
ChemCatChem 2015, 7, 62-64.
[34] F. Mao, D. Sui, Z. Qi, H. Fan, R. Chen, J. Huang, RSC Adv. 2016, 6,
94068-94073.
pathway regarding the reductive alkylation of nitriles with carbonyl
compounds as shown in Scheme 2, top. Mechanistics
investigations were carried out under the given conditions
(Scheme 2, bottom), product and intermediates are obtained in
the yields listed. We used milder reaction conditions to better
distinguish between the rates of the individual reaction steps. The
hydrogenation of the nitrile proceeds slowly in comparison to
condensation and imine hydrogenation and is probably the rate-
determining step in the product formation sequence. The
benzaldehyde is slowly converted to the corresponding alcohol
(23 % under the conditions given) if no nitrile is present. No
hydrogenation of benzaldehyde to the corresponding alcohol was
observed if the reaction is performed in the presence of nitriles.
[35] X. Cui, K. Liang, M. Tian, Y. Zhu, J. Ma, Z. Dong, J. Colloid Interface
Sci. 2017, 501, 231-240.
[36] L.-F. Chen, Q. Wu, Science 2017, 358, 304-305.
[37] H. Wu, C. Shen, C. Xia, L. He, Sci. China Mat. 2017, 60, 1269-1271.
[38] L. Jiang, P. Zhou, Z. Zhang, Q. Chi, S. Jin, New J. Chem. 2017, 41,
11991-11997.
We thank the Deutsche Forschungsgemeinschaft (KE 756/33-1)
for financial support. In addition, the authors thank F. Puchtler for
powder X-ray diffraction, C. Denner for EDX measurements and
S. Hüttner for the X-ray photoelectron spectroscopy. Furthermore,
we thank the Elite-Network-Bavaria and the DAAD (Melbourne-
Bayreuth Network of Colloids and Polymers) for financial support.
[39] P. Zhou, L. Jiang, F. Wang, K. Deng, K. Lv, Z. Zhang, Sci. Adv. 2017,
3, e1601945.
[40] Z. Yuan, B. Liu, P. Zhou, Z. Zhang, Q. Chi, J. Catal. 2019, 370, 347-
356.
[41] T. Senthamarai, V. G. Chandrashekhar, M. B. Gawande, N. V.
Kalevaru, R. Zbořil, P. C. J. Kamer, R. V. Jagadeesh, M. Beller, Chem.
Sci. 2020, 11, 2973-2981.
The authors declare no conflict of interest.
[42] D. J. Segobia, A. F. Trasarti, C. R. Apesteguía, J. Catal. 2019, 380,
178-185.
[43] L. F. B. Ribeiro, O. Flores, P. Furtat, C. Gervais, R. Kempe, R. A. F.
Machadoa, G. Motz, J. Mater. Chem. A. 2017, 5, 720–729.
[44] C. Bäumler, C. Bauer, R. Kempe, ChemSusChem 2020, 13, 3110-
3114.
Keywords: Amines • catalysis • cobalt • hydrogenation • nitriles
[1]
[2]
[3]
K. Weissermel, H.-J. Arpe, H.-J. in Industrial Organic Chemistry, Wiley-
VCH, Weinheim, 2008.
R. Vardanyan, V. Hruby in Synthesis of Best-Seller Drugs, Academic
Press, 2016.
S. A. Lawrence in Amines: Synthesis, Properties and Applications,
Cambridge University Press, 2004.
[4]
[5]
[6]
A. Corma, J. Navas, M. J. Sabater, Chem. Rev. 2018, 118, 1410–1459.
T. Irrgang, R. Kempe, Chem. Rev. 2019, 119, 2524–2549.
K. Murugesan, T. Senthamarai, V. G. Chandrashekhar, K. Natte, P. C.
J. Kamer, M. Beller, R. V. Jagadeesh, Chem. Soc. Rev. 2020, 49,
6273-6328.
[7]
[8]
[9]
T. Irrgang, R. Kempe, Chem. Rev. 2020, 120, 9583-9674.
P. Kalck, M. Urrutigoïty, Chem. Rev. 2018, 118, 3833–3861.
L. Huang, M. Arndt, K. Gooßen, H. Heydt, L. J. Gooßen, Chem. Rev.
2015, 115, 2596–2697.
[10] T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev.
2008, 108, 3795–3892.
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10.1002/chem.202004755
Chemistry - A European Journal
COMMUNICATION
A cobalt catalyst was developed, which is nanostructured, reusable, and easy to handle. It mediates the selective reductive alkylation
of nitriles with carbonyl compounds. The key to a broad scope and the tolerance of numerous functional groups, including hydrogenation
sensitive examples, is the earth-abundant metal in combination with a porous N-doped SiC catalyst support material.
6
This article is protected by copyright. All rights reserved.